Acute febrile neutrophilic dermatosis

Acute Febrile Neutrophilic Dermatosis Acute febrile neutrophilic dermatosis, or Sweet's syndrome, usually occurs in middle-aged women with a preceding upper respiratory tract infection. In about 20 percent of reported cases, the syndrome is associated with an underlying malignancy, most frequently acute myelogenous leukemia. A dense infiltrate of mature neutrophils is seen in the middle and upper portions of the dermis. corticosteroid therapy produces rapid improvement of all manifestations of the syndrome. The clinical and histologic features of acute febrile neutrophilic dermatosis were first described by Sweet in 1964.(1) This condition, also known as Sweet's syndrome, is characterized by painful, erythematous cutaneous plaques, pyrexia, neutrophilia and a neutrophilic dermal infiltrate.(2-6) Extracutaneous manifestations have been observed in the muscles, joints, kidneys, eyes, lungs and liver.(7) Laboratory findings usually include an increased serum neutrophil count, an elevated erythrocyte sedimentation rate and negative bacterial, fungal and viral cultures of the skin lesions.(2-6) An associated hematologic malignancy or solid tumor occurs in approximately 20 percent of reported cases.(8) All manifestations of the idiopathic and malignancy-associated syndromes respond dramatically to corticosteroid therapy.(2-6)

Illustrative Case

A febrile 48-year-old woman presented for the evaluation of multiple painful skin lesions. Three weeks previously, she had had an upper respiratory tract infection with a sore throat; at that time, a painful lesion had appeared on her shoulder. During the week before presentation, she developed additional lesions on her left arm and both hands, conjunctival inflammation, joint pains, a swollen left hand and a temperature of 38.3|C (101|F).

Physical examination revealed several erythematous, tender plaques and nodules, ranging in diameter from 1 to 5 cm, on the left shoulder, the left arm and both hands. Some of the lesions were pseudovesicular in appearance. The left wrist was swollen, with a diminished range of motion. The remainder of the physical examination was normal.

Laboratory evaluation revealed neutrophilia: 9,600 leukocytes per mm cube (9.6 X 10 raised to 9 per L), with 78 percent (0.78) neutrophils. The erythrocyte sedimentation rate was elevated to 46 mm per hour. Urinalysis revealed three to five leukocytes and erythrocytes per high-power field, with no proteinuria. Hemoglobin, hematocrit, platelet count and serum chemistries were normal. Chest radiograph and blood cultures were negative. Subsequent clinical and laboratory evaluations did not reveal an underlying malignancy.

Biopsy of a skin lesion was performed. Microscopic examination showed subepidermal edema and a dermal infiltrate composed predominantly of neutrophils. Histologic changes of vasculitis were absent. Examination of the biopsy specimen confirmed the diagnosis of acute febrile neutrophilic dermatosis.

Systemic corticosteroid therapy (60 mg of oral prednisone per day) was initiated. Rapid resolution of the patient's fever, conjunctivitis and arthritis, as well as dramatic improvement of the skin lesions, occurred within two to three days. The prednisone dosage was gradually tapered over two months without recurrence of symptoms or lesions.

Clinical Features

The typical clinical presentation of idiopathic acute febrile neutrophilic dermatosis includes fever and tender, red pseudovesicular plaques on the upper extremities, head and/or neck. Laboratory studies generally reveal an elevated neutrophil count.

Most patients with idiopathic acute febrile neutrophilic dermatosis are otherwise healthy middle-aged women who have had a recent upper respiratory tract infection. The idiopathic form of the syndrome occurs less frequently in men(3,9) and children.(10,11) Although the syndrome usually occurs in patients between 30 and 60 years of age, skin lesions have appeared in patients as young as three months and as old as 85 years.(6,10,12)

In addition to the characteristic morphologic and histologic cutaneous lesions, 80 to 90 percent of patients with idiopathic acute febrile neutrophilic dermatosis have pyrexia, 80 percent have neutrophilia and 90 percent have an elevated erythrocyte sedimentation rate.(3,4,6) If untreated, the idiopathic form of the syndrome resolves spontaneously within one to three months.(2,3) However, rapid improvement of symptoms and lesions occurs two to three days after the initiation of corticosteroid therapy.(5,7)

Acute febrile neutrophilic dermatosis is associated with a hematologic malignancy (most commonly acute myelogenous leukemia) or a solid tumor (usually a carcinoma of the genitourinary organs) in nearly 20 percent of cases. The malignancy-associated syndrome occurs equally in men and women and is characterized by severe cutaneous lesions, fever and an elevated erythrocyte sedimentation rate.

More than 80 percent of patients with hematologic malignancies also have anemia, 68 percent have an abnormal platelet count and 53 percent have a normal to low neutrophil count. Because of the underlying disorder or chemotherapy-induced bone marrow suppression, blood counts may not be elevated in patients with the malignancy-associated syndrome. Regardless of the response of the associated neoplasm to tumor-directed therapy, corticosteroids dramatically improve all manifestations of acute febrile neutrophilic dermatosis in these patients.(7,8)

The cutaneous lesions of acute febrile neutrophilic dermatosis range in diameter from 5 mm to 12 cm.(2,5) The lesions are usually erythematous plaques and nodules, although vesicles, bullae and even ulcerations occasionally occur. The upper extremities, head and neck are most commonly affected. Less frequently, lesions appear on the lower extremities, trunk and back.(3,4,6) Rarely, oral mucous membrane lesions are present.(7,9)

Single or multiple recurrences of symptoms and lesions have been reported in 30 percent of patients with idiopathic acute febrile neutrophilic dermatosis and in 50 to 69 percent of patients with the malignancy-associated syndrome.(3,4,6,8) Symptoms and lesions tend to recur when the corticosteroid is tapered too quickly or the underlying cancer is recurring. The lesions of patients with the idiopathic syndrome generally have a less severe morphology, a typical location and a lower incidence of recurrence than the lesions of patients with the malignancy-associated syndrome.

Manifestations of acute febrile neutrophilic dermatosis have been observed in the musculoskeletal,(13,14) renal,(3,12,15) ocular,(3,16,17) pulmonary(18) and hepatic(15) systems (Table 1). The extracutaneous manifestations and skin lesions of acute febrile neutrophilic dermatosis usually appear simultaneously and respond similarly to corticosteroid therapy.(8)

Histologic Features

The pathognomonic histologic feature of acute febrile neutrophilic dermatosis is the presence of a dense infiltrate of mature neutrophils in the middle and upper portions of the dermis. The infiltrate also may contain lymphocytes, histiocytes and eosinophils. Vesicle formation secondary to papillary dermis edema, neutrophil nuclear dust and endothelial cell swelling may be present in the dermis. The epidermis is usually normal, although it may be mildly acanthotic or slightly hyperkeratotic. Importantly, there are no histologic features of a true leukocytoclastic vasculitis, no primary or metastatic tumor cells, and no bacterial, mycobacterial or fungal organisms.(1,6-8,17)

Pathogenesis

The etiology of acute febrile neutrophilic dermatosis is uncertain, and a number of questions remain unanswered. Does acute febrile neutrophilic dermatosis have a single cause or is it the result of multiple concordant mechanisms? Do the skin lesions represent a specific isomorphic cutaneous response to various nonspecific external stimuli?(2,3,6) Do the increased blood and dermal neutrophils have a primary role in the pathogenesis of this disease?(14,19,20)

Several investigators have suggested that an immunologic mechanism (by means of a Type I,(6,12) a Type II(10) or even a Type III(10,14) immune reaction) has an etiologic role in the pathogenesis of acute febrile neutrophilic dermatosis. It has also been suggested that the inappropriate secretion of cytokines (epidermal cell thymocyte-activating factor, interleukin-1 and/or granulocyte colony-stimulating factor) may account for many of the signs and symptoms of acute febrile neutrophilic dermatosis, including the pyrexia, neutrophilia and increased erythrocyte sedimentation rate.(8)

Differential Diagnosis

Several disorders that occur in otherwise healthy individuals and/or cancer patients may mimic acute febrile neutrophilic dermatosis (Table 2).(7,8) The possibility of a cutaneous neoplastic lesion or an infectious process must be considered in the evaluation of a new erythematous plaque in a patient with a previously diagnosed malignancy.(7,8,11,21,22) In this setting, it is essential to obtain biopsy specimens of cutaneous lesions for histologic evaluation and bacterial and fungal cultures.

Cutaneous manifestations similar to those seen in acute febrile neutrophilic dermatosis may be present in other conditions, including inflammatory diseases,(4,11,22) reactive erythemas,(11-13) systematic diseases,(11,13,22) vasculitides(11-13) and other disorders.(4,12,22) Additional clinical characteristics and histologic features enable these conditions to be readily distinguished from acute febrile neutrophilic dermatosis.(7,8) Therefore, microscopic evaluation of a lesional skin biopsy specimen is recommended when the diagnosis of acute febrile neutrophilic dermatosis is entertained.

Treatment

Once the diagnosis of acute febrile neutrophilic dermatosis has been confirmed, systemic corticosteroid therapy (1 mg per kg per day, administered orally) is the treatment of choice. Symptoms often resolve within hours of the initiation of corticosteroid therapy, and skin lesions usually improve dramatically within two to three days in patients with either idiopathic or malignancy-associated acute febrile neutrophilic dermatosis. To prevent exacerbations and recurrent episodes of the syndrome, it is important to taper the corticosteroid gradually over four to six weeks.(6-8)

Colchicine(23) and potassium iodide (either alone or in a corticosteroid-sparing manner)(16) are alternative, efficacious therapies for acute febrile neutrophilic dermatosis. In a small number of patients, indomethacin (Indocin),(24) clofazimine (Lamprene),(1) and dapsone(20) have been effective. Antibiotics have no beneficial effect on the manifestations of acute febrile neutrophilic dermatosis.(7,8)

TABLE 1

Extracutaneous Manifestations of Acute Febrile Neutrophilic Dermatosis Musculoskeletal Myalgias Arthralgias Renal Proteinuria Hematuria Renal insufficiency Glomerulonephritis Acute renal failure Ocular Iritis Episcleritis Inflammation or hyperemia of conjunctiva Pulmonary Pulmonary infiltrates on chest radiograph Parenchymal changes on lung biopsy Hepatic Liver biopsy abnormalities

TABLE 2

Disorders Mimicking Acute Febrile Neutrophilic Dermatosis Cutaneous neoplastic lesions Chloroma Leukemia cutis Lymphorra Metastatic tumors Infections Bacterial sepsis Cellulitis Cutaneous tuberculosis Deep mycosis Erysipelas Leprosy Lymphangitis Thrombophlebitis Viral exanthems Inflammatory diseases Panniculitis Pyodermagangrenosum Reactive erythemas Erythema nodosum Erythema multiforme Urticaria Systemic diseases Behcet's syndrome Bowel bypass syndrome Dermatomyositis Familial Mediterranean fever Lupus erythematosus Vasculitides Erythema elevatum diutinum Leukocytoclastic vasculitis Periarteritis nodosa Other disorders Drug eruptions Granuloma faciale Halogenoderma

PHOTO : Cutaneous lesions of idiopathic acute febrile neutrophilic dermatosis in a middle-aged

PHOTO : woman with pyrexia, neutrophilia and a recent upper respiratory tract infection.

PHOTO : Erythematous plaque, 5 cm in diameter, with a pseudovesicular appearance on the left

PHOTO : shoulder of the patient.

PHOTO : Nodular lesion, 1 cm in diameter, on the lateral left arm of the patient. In both

PHOTO : idiopathic and malignancy-associated acute febrile neutrophilic dermatosis, lesions most

PHOTO : commonly develop on the upper extremities.

PHOTO : Painful, erythematous, pseudovesicular plaques of acute febrile neutrophilic dermatosis

PHOTO : on the hand of the patient. These lesions improved rapidly after corticosteroid therapy

PHOTO : was initiated.

PHOTO : Closer view of lesions on the hand of the same patient. REFERENCES (1)Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964;76:349-56. (2)Crow KD, Kerdel-Vegas F, Rook A. Acute febrile neutrophilic dermatosis. Sweet's syndrome. Dermatologica 1969;139:123-34. (3)Gunawardena DA, Gunawardena KA, Ratnayaka RM, Vasanthanathan NS. The clinical spectrum of Sweet's syndrome (acute febrile neutrophilic dermatosis)--a report of eighteen cases.Br J Dermatol 1975;92:363-73. (4)Storer JS, Nesbitt LT Jr, Galen WK, DeLeo VA. Sweet's syndrome. Int J Dermatol 1983;22:8-12. (5)Callen JP. Acute febrile neutrophilic dermatosis (Sweet's syndrome) and the related conditions of "bowel bypass" syndrome and bullous pyoderma gangrenosum. Dermatol Clin 1985;3:153-63. (6)Greer KE, Cooper PH. Sweet's syndrome (acute febrile neutrophilic dermatosis). Clin Rheum Dis 1982;8:427-41. (7)Cohen PR, Kurzrock R. Sweet's syndrome and malignancy. AM J Med 1987;82:1220-6. (8)Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet's syndrome: review of the world literature. J Clin Oncol 1988;6:1887-97. (9)Driban NE, Alvarez MA. Oral manifestations of Sweet's syndrome. Dermatologica 1984;169:102-3. (10)Itami S, Nishioka K. Sweet's syndrome in infancy. Br J Dermatol 1980;103:449-51. (11)Hazen PG, Kark EC, Davis BR, Carney JF, Kurczynski E. Acute febrile neutrophilic dermatosis in children. Report of two cases in male infants. Arch Dermatol 1983;119:998-1002. (12)Saxe N, Gordon W. Acute febrile neutrophilic dermatosis (Sweet's syndrome). Four case reports. S Afr Med J 1978;53:253-6. (13)Krauser RE, Schumacher HR. The arthritis of Sweet's syndrome. Arthritis Rheum 1975;18:35-41. (14)Trentham DE, Masi AT, Bale GF. Arthritis with an inflammatory dermatosis resembling Sweet's syndrome. Report of a unique case and review of the literature on arthritis associated with inflammatory dermatoses. Am J Med 1976;61:424-32. (15)Matta M, Malak J, Tabet E, Kurban AK. Sweet's syndrome: systemic associations. Cutis 1973;12:561-5. (16)Myatt AE, Baker DJ, Byfield DM. Sweet's syndrome: a report on the use of potassium iodide. Clin Exp Dermatol 1987;12:345-9. (17)Going JJ, Going SM, Myskow MW, Beveridge GW. Sweet's syndrome: histological and immunohistochemical study of 15 cases. J Clin Pathol 1987;40:175-9. (18)Lazarus AA, McMillan M, Miramadi A. Pulmonary involvement in Sweet's syndrome (acute febrile neutrophilic dermatosis). Pre-leukemic and leukemic phases of acute myelogenous leukemia. Chest 1986;90:922-4. (19)Nunzi E, Crovato F, Dallegri F, Patrone F, Cormane RH. Immunopathological studies on a case of Sweet's syndrome. Dermatologica 1981;163:393-400. (20)Aram H. Acute febrile neutrophilic dermatosis (Sweet's syndrome). Response to dapsone. Arch Dermatol 1984;120:245-7. (21)Cohen PR, Rapini RP, Beran M. Infiltrated blue-gray plaques in a patient with leukemia. Chloroma (granulocytic sarcoma). Arch Dermatol 1987;123:251,254. (22)Hoppes DA. Sweet's syndrome (acute febrile neutrophilic dermatosis): report of two cases. J Am Osteopath Assoc 1983;82:492-7. (23)Suehisa S, Tagami H, Inoue F, Matsumoto K, Yoshikuni K. Colchicine in the treatment of acute febrile neutrophilic dermatosis (Sweet's syndrome). Br J Dermatol 1983;108:99-101. (24)Hoffman GS. Treatment of Sweet's syndrome (active febrile neutrophilic dermatosis) with indomethacin. J Rheumatol 1977;4:201-6.

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